Histone methyltransferases (HMTs), a class of enzymatic “writers” of epigenetic marks, have recently emerged as targets of potential therapeutic value. They catalyze the methylation of histone lysines and arginines utilizing Sadenosyl-methionine (SAM) as the cofactor/methyl-source. This process can result in either the activation or repression of transcription. Dysregulation of methylation at specific histone sites (alterations in the “histone code”) has been implicated in many cancers. Hence, targeting HMT activity has been the subject of much investigation in the field of oncology.
One such HMT is Euchromatic histone methyltransferase 2 (EHMT2), also known as G9a. G9a is primarily responsible for the dimethylation of lysine 9 on histone H3 (H3K9). Several reports have highlighted its link to a variety of cancers, including hepatocellular carcinoma, B cell acute lymphoblastic leukemia, and lung cancers.
While small molecule inhibitors of G9a have been reported as early as 2005, their effectiveness has largely been unsuccessful. Accordingly, there is a need in the art for highly specific inhibitors of G9a that have reduced cytotoxicity to non-tumor cells, and can be combined with other known anti-tumor therapies.